Vascular Health and Risk Management

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Type 2 diabetes: postprandial hyperglycemia

and increased cardiovascular risk
This article was published in the following Dove Press journal:
Vascular Health and Risk Management
5 March 2010
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Ajikumar V Aryangat
John E Gerich
University of Rochester, Rochester,
New York, USA

Abstract: Hyperglycemia is a major risk factor for both the microvascular and macrovascular
complications in patients with type 2 diabetes. This review summarizes the cardiovascular results
of large outcomes trials in diabetes and presents new evidence on the role of hyperglycemia, with
particular emphasis on postprandial hyperglycemia, in adverse cardiovascular outcomes in
patients with type 2 diabetes. Treatment options, including the new dipeptidyl peptidase-4
inhibitors and glucagon-like peptide-1 mimetics that primarily target postprandial hyperglycemia, are also discussed. Hyperglycemia increases cardiovascular mortality, and reducing
hyperglycemia lowers cardiovascular risk parameters. Control of both fasting and postprandial
hyperglycemia is necessary to achieve optimal glycated hemoglobin control. Therefore, antihyperglycemic agents that preferentially target postprandial hyperglycemia, along with those
that preferentially target fasting hyperglycemia, are strongly suggested to optimize individual
diabetes treatment strategies and reduce complications.
Keywords: postprandial hyperglycemia, diabetes mellitus, drugs, cardiovascular risk

Introduction

Correspondence: John E Gerich

University of Rochester Medical Center,
General Clinical Research Center,
601 Elmwood Avenue, Box MED/CRC,
Rochester, New York 14642, USA
Tel +1 (585) 275-5295
Fax +1 (585) 461-4737
Email johngerich@compuserve.com

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Several landmark clinical trials have convincingly demonstrated that hyperglycemia is

associated with the microvascular complications of diabetes.13 These trials, along with
epidemiological evidence, have provided the basis for treatment targets and algorithms
recommended by the American Diabetes Association (ADA), the American Association
of Clinical Endocrinologists (AACE), and the European Association for the Study of
Diabetes (EASD).46 Adequacy of glycemic control is almost universally assessed by
glycated hemoglobin (HbA1c) a measure of hemoglobin glycation over the erythrocyte life span that is proportional to the mean plasma glucose level over the preceding
2 to 3 months. An HbA1c 7% is recommended by the ADA/EASD and 6.5% by the
AACE.46 The mean value for individuals with normal glucose tolerance is 5.0% (upper
limit of normal is 6.0%). HbA1c can be communicated with patients using estimated
average glucose (eAG; HbA1c 5% = eAG 5.4 mmol/L, 97 mg/dL), so that they better
understand how their blood glucose monitor readings are related to HbA1c.4
In addition to HbA1c, patients and physicians usually monitor and treat fasting plasma
glucose (FPG) levels, but ignore or de-emphasize postprandial glucose (PPG) levels.
There is no evidence that fasting hyperglycemia is more deleterious than postprandial
hyperglycemia. Recent evidence, however, strongly suggests that control of postprandial
hyperglycemia may be necessary to achieve HbA1c targets 7%.7 Considerable data
have accumulated indicating that elevated PPG levels, even in the absence of fasting
hyperglycemia, increase the risk for cardiovascular (CV) disease (CVD). This article
Vascular Health and Risk Management 2010:6 145155
145
2010 Aryangat and Gerich, publisher and licensee Dove Medical Press Ltd. This is an Open Access article
which permits unrestricted noncommercial use, provided the original work is properly cited.

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Aryangat and Gerich

discusses and updates epidemiological and experimental

studies linking postprandial hyperglycemia to CVD, and
therapeutic approaches, both available and in development.

Hyperglycemia and CVD

In people with type 2 diabetes, macrovascular disease, in particular CVD, is the major source of morbidity and mortality.
The pathogenesis of CVD is complex and multifactorial.
Smoking, obesity, dyslipidemia, and hypertension were
considered the major traditional risk factors. Now diabetes itself is considered an important independent risk factor.8 Having diabetes increases the risk for CVD mortality
more than two-fold.9 For example, in the INTERHEART study,
a case-control study that assessed risk factors of coronary
artery disease (CAD) worldwide in nearly 30,000 subjects,
diabetes increased the odds ratio of having an acute myocardial infarction (MI) to 4.26 (99% confidence interval [CI],
3.51 to 5.18) in women and to 2.67 (99% CI, 2.36 to 3.02) in
men (Table 1), making diabetes as important a risk factor as
smoking, hypertension, obesity, and dyslipidemia.10
Numerous epidemiological studies have demonstrated a
correlation between risk for CVD and plasma glucose levels
(both fasting and postprandial) or HbA1c values.11 The relationship between PPG and CV events persists even in the context of HbA1c levels in the nondiabetic range.11,12 Moreover, the
Funagata Diabetes Study showed that the cumulative survival
rates from CVD of impaired glucose tolerance (IGT) and
diabetes were reduced comparably, whereas the cumulative
survival rate from CVD of impaired fasting glucose (IFG)
Table 1 Association of risk factors with acute myocardial infarction in men and women
Risk factor

Sex

Odds ratio (99% CI)a

Diabetes

4.26 (3.515.18)

2.67 (2.363.02)

2.95 (2.573.39)

2.32 (2.122.53)

2.86 (2.363.48)

3.05 (2.783.33)

2.26 (1.902.68)

2.24 (2.032.47)

4.42 (3.435.70)

3.76 (3.234.38)

Hypertension
Current smoking
Abdominal obesity
ApoB/ApoA1 ratiob

Adjusted for age, sex, and geographic area.

ApoB/ApoA1 ratio as an index of dyslipidemia.
Adapted from The Lancet, 364,Yusuf S, Hawken S, unpuu S, et al; for the INTERHEART
Study Investigators. Effect of potentially modifiable risk factors associated with
myocardial infarction in 52 countries (the INTERHEART study): case-control study,
937952.10 Copyright (2004), with permission from Elsevier.
Abbreviations: F, female; M, male.
a

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was not.13 This suggests that IGT (or postprandial glycemia)

is a more important CVD risk factor than IFG.
Epidemiological data suggest a strong link between CV
risk and glucose control, but by nature of study design, cannot determine causality. Controlled clinical trials can determine causality and have examined the effects of glycemic
control on vascular complications. The United Kingdom
Prospective Diabetes Study (UKPDS),1 the Diabetes Control
and Complications Trial (DCCT),3 the Action to Control
Cardiovascular Risk in Diabetes (ACCORD),14 and the Action
in Diabetes and Vascular Disease: Preterax and Diamicron
Modified Release Controlled Evaluation (ADVANCE)2 were
landmark controlled clinical trials that evaluated the benefits
of intensive glucose control on diabetes complications. The
UKPDS demonstrated a 25% risk reduction for microvascular
complications (P = 0.0099) and a 16% risk reduction for MI
(P = 0.052) in intensively treated patients.1 Moreover, during
a 10-year poststudy monitoring period, the UKPDS follow-up
data demonstrated a persistent 15% risk reduction for MI
(P = 0.01) and a 13% risk reduction for all-cause mortality
(P = 0.007; Figure 1) despite a convergence in glycemic
control levels between treatment groups.15
The DCCT follow-up study yielded a similar finding.
The DCCT consisted of 1441 patients with type 1 diabetes
randomized to intensive or conventional therapy for a mean
of 6.5 years 1983 through 1993.3,16 Ninety-three percent
of patients from the DCCT were followed until February 1, 2005, (mean 17-year follow-up) in the observational
Epidemiology of Diabetes Interventions and Complications
(EDIC) study. Intensive treatment reduced the risk of any
CVD event by 42% (95% CI, 9% to 63%; P = 0.02) and
the risk of nonfatal MI, stroke, or death from CVD by 57%
(95% CI, 12% to 79%; P = 0.02).
The ACCORD14 and ADVANCE2 trials evaluated intensive blood glucose control below the current recommended
levels of HbA1c and its impact on CV events. The ACCORD
study consisted of 10,251 patients with type 2 diabetes with
a median baseline HbA1c of 8.1% who were given intensive
therapy to target HbA1c below 6% versus standard therapy
(HbA1c = 7.0% to 7.9%). Thirty-five percent of patients had
history of a previous CV event. The intensively treated arm
of the study was terminated early because of higher mortality
of 257 patients in this treatment group versus 203 patients in
the standard therapy group. However, nonfatal MI occurred
less often in the intensive group than in the standard group
(P = 0.004). Although overall difference in macrovascular
events in ACCORD was not statistically significant between
intensive and standard therapy, patients in the intensive

Vascular Health and Risk Management 2010:6

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T2D: postprandial hyperglycemia and increased CV risk

Any diabetes
end point

Microvascular
disease

Myocardial
infarction

All-cause
mortality

Intervention trial completed in 1997

6
P = 0.44

Relative risk reduction (%)

10
20

12
P = 0.029

16
P = 0.052
25
P = 0.0099

30
40

Post-trial monitoring completed in 2007

0
10
20

9
P = 0.040

30

15
P = 0.01

13
P = 0.007

24
P = 0.001

40
Figure 1 Significant relative risk reduction in microvascular disease and any diabetes end point continued during 10 years of post-trial follow-up. Significant emergent risk
reductions in myocardial infarction and all-cause mortality were observed only with extended follow-up.1,15
Adapted from The Lancet, 352, UK Prospective Diabetes Study (UKPDS) Group, Intensive blood-glucose control with sulphonylureas or insulin compared with conventional
treatment and risk of complications in patients with type 2 diabetes (UKPDS 33), 837853.1 Copyright (1998), with permission from Elsevier.

therapy arm with no history of prior CV events or whose

baseline HbA1c level was 8% had significantly fewer fatal
or nonfatal CV events than the standard therapy arm. In these
subgroups, intensive lowering of HbA1c was beneficial.14
The ADVANCE trial2 studied 11,140 patients with type 2
diabetes randomized to receive standard therapy or gliclazide
plus other medications to achieve HbA1c of 6.5% in the
intensive control arm. With a median 5-year follow-up, mean
HbA1c was lower in the intensive control group (6.5%) than in
the standard control group (7.3%). Intensive control reduced
the incidence of combined major macro- and microvascular
events (18.1% versus 20.0% with standard control; hazard
ratio [HR], 0.90; 95% CI, 0.82 to 0.98; P = 0.01), as well as that
of major microvascular events (9.4% versus 10.9%; HR, 0.86;
95% CI, 0.77 to 0.97; P = 0.01), primarily because of a reduction in the incidence of nephropathy (4.1% versus 5.2%; HR,
0.79; 95% CI, 0.66 to 0.93; P = 0.006). The ADVANCE trial,
while positive for microvascular complications, had an event
rate too low to have the statistical power to show a benefit of
intensive glucose control on macrovascular complications.
The Veterans Affairs Diabetes Trial (VADT)17 randomized
1791 patients with type 2 diabetes who had suboptimal
control on oral medications or insulin with a median HbA1c of
8.4% for intensive glucose control or standard therapy, with a

Vascular Health and Risk Management 2010:6

goal of an absolute reduction of 1.5% HbA1c in the intensive

versus standard therapy group. A major CV event, the primary
outcome, occurred in 264 patients in the standard therapy
group and 235 patients in the intensive therapy group (HR
in the intensive therapy group, 0.88; 95% CI, 0.74 to 1.05;
P = 0.14). The incidence of primary outcome was not significantly lower in the intensive arm, but a subgroup analysis
indicated that patients who had diabetes less than 12 years
derived CV benefit from intensive glycemic control.18 Also,
an embedded ancillary study within the main VADT showed
that patients with previous history of increased baseline
coronary or aortic calcium scores benefited less compared
with patients who had low calcium scores.18
Together, the ACCORD,14 ADVANCE,2 and VADT17
studies showed significant CV benefit in patients who had
lower baseline HbA1c, no prior history of CAD, and shorter
history of diabetes. Both the DCCT and UKPDS primary
intervention studies also demonstrated long-term macrovascular benefits (10 year follow-up).15,16 Taken together, these
studies illustrate that intensive glycemic control early in the
course of diabetes is important in achieving CV benefit and
provides guidance in terms of stratification of patients target
glycemic control. Thus, achieving a goal of HbA1c 7% is
recommended, but a less intense target should be planned for

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Aryangat and Gerich

patients with history of severe CVD, severe hypoglycemia, or

advanced microvascular or macrovascular disease complications. In addition to addressing diabetes control, physicians
must optimize other modifying factors of CVD, including
blood pressure, hyperlipidemia, obesity, smoking cessation,
regular exercise, and healthy diet.18 In the future, development of a risk profile and stratification will be important
in customizing and guiding each patients glycemic target
and optimizing the benefits of intensive glucose control.

Mechanisms of hyperglycemiainduced CV damage

Acute hyperglycemia has been linked to endothelial dysfunction. Monnier et al19 reported that the urinary excretion
rate of 8-iso-prostaglandin F2, a marker of oxidative stress,
correlated best with the glycemic variability assessed from
the mean amplitude of glycemic excursions. To add another
level of complexity, Ceriello et al20 showed that not only
was hyperglycemia associated with endothelial dysfunction
in patients with and without type 2 diabetes, but also that
oscillating glucose levels in 6-hour increments led to even
greater dysfunction over time. Other studies also provided
evidence that postprandial fluctuations, in addition to absolute increases in glycemia, contribute to oxidative stress
and endothelial dysfunction.2123 Endothelial dysfunction
seems to be affected via the vascular glycocalyx (an extracellular matrix of endothelial cell-derived proteoglycans,
glycoproteins, and absorbed plasma proteins that act as a
mechanosensor/mechanotransducer of blood flow and vascular shear stress) in a predominantly nitric oxide-dependent
manner that promotes endothelial response to stimuli.2426
Nieuwdorp et al26 utilized several techniques (eg, hyperglycemic clamp, flow-mediated dilation, glycocalyx tracers, and
laboratory analytical tests) to assess endothelial function and
coagulation parameters after hyperglycemic challenge in 10
healthy males. After glucose infusion, glycocalyx volume
was decreased, mechanotransduction of flow-dependent
arterial dilation was attenuated, and levels of prothrombin
activation fragment F1 + 2, a factor that initiates coagulation
cascades, were increased during hyperglycemia. Moreover,
reducing PPG has been reported to improve endothelial
dysfunction.23 Oxidative stress caused by acute PPG spikes
can contribute to macrovascular damage through oxidation
of low-density lipoprotein, exacerbation of endothelial dysfunction, and other proatherogenic mechanisms. An overview
of the complex interaction between factors that contribute
to macrovascular complications of diabetes is presented in
Figure 2.11,27

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Management of postprandial
hyperglycemia
Postprandial glucose control is the rate-limiting step when
optimizing blood glucose levels, as demonstrated in the study
by Woerle et al.7 This prospective interventional trial assessed
the relative contributions of FPG and PPG in achieving recommended HbA1c goals. There were 164 patients with type 2 diabetes with HbA1c levels 7.5% (mean 8.7% 0.1) with target
reductions of FPG to 5.6 mmol/L (100 mg/dL) and PPG
at 90 minutes to 7.8 mmol/L (140 mg/dL). The study
showed that when FPG (but not PPG) was at target, only 64%
of patients achieved HbA1c 7%, whereas when both FPG and
PPG were at target, 94% achieved HbA1c 7%. FPG values
did not differ in patients with HbA1c above or below 7%. PPG
accounted for 90% of HbA1c values when HbA1c was 6.2%,
but only 40% when HbA1c was 8.9%.7 These results further
illustrate the importance of PPG in achieving better control
of diabetes, consistent with an earlier study conducted by
Monnier et al.28 Most recently, results from the 4-T trial
(Treating to Target in Type 2 Diabetes) indicated preprandial
treatment with a rapid-acting insulin analogue resulting in
significant decreases in PPG (85 59 mg/dL) compared
with basal and biphasic insulin regimens (61 58 mg/dL and
67 50 mg/dL, respectively).29 However, while preprandial
treatment with a rapid-acting insulin analogue resulted in
significant reductions in HbA1c from baseline (1.4% 0.1),
comparisons with basal and biphasic insulin regimens were
not significantly different (1.3% 0.1 and 1.2% 0.1,
respectively). It is interesting to note that no differences were
found in FPG levels among the treatment groups.29
Furthermore, randomized controlled trials with agents
that primarily target postprandial hyperglycemia have
demonstrated CV benefit. The Study to Prevent NonInsulin-Dependent Diabetes Mellitus (STOP-NIDDM) Trial
showed that treating postprandial hyperglycemia with acarbose in patients with IGT reduced CV events.30 PPG levels
seen in diabetic patients correlate with carotid intima-media
thickness (CIMT),31 and treatment with antihyperglycemic
agents such as nateglinide and acarbose which target postprandial glycemia reduces progression of CIMT.32,33 In addition, optimal control of postprandial hyperglycemia has been
associated with improved coronary blood flow34 as well as
possible reversal of myocardial perfusion abnormalities.35

ADA, IDF, and AACE recommendations

The ADA in its Standards of Medical Care in Diabetes20094
acknowledges that elevated PPG values are associated with
increased CV risk independent of FPG and that the relative

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T2D: postprandial hyperglycemia and increased CV risk

Figure 2 Mechanisms by which hyperglycemia induces mitochondrial overproduction of superoxide and activates 4 major pathways of hyperglycemic damage.11,27
Copyright 2005 American Diabetes Association from Diabetes. 2005;54:16151625.27 Adapted with permission from the American Diabetes Association.

contribution of postprandial hyperglycemia to HbA1c is greater

at HbA1c levels that are closer to 7%. The ADA recommends
that individuals who have preprandial glucose values within
target, but have HbA1c values above target, should monitor
PPG 1 to 2 hours after the start of a meal. Treatment aimed
at reducing PPG values to 10 mmol/L (180 mg/dL) will
likely lower HbA1c and may improve outcomes.4
The International Diabetes Federation (IDF) recommends that patients with diabetes manage their HbA1c
levels to be 6.5% by addressing both FPG and PPG.
The guidelines recommend that PPG levels not exceed
7.8 mmol/L (140 mg/dL) during the 2 hours postmeal.
The frequency of self-monitoring to track PPG levels should
be planned on an individual basis.36 AACE guidelines are
similar to those of the IDF, suggesting HbA1c 6.5%, FPG

Vascular Health and Risk Management 2010:6

6 mmol/L (110 mg/dL), and 2-hour PPG 7.8 mmol/L

(140 mg/dL).5

Treatment considerations

Nonpharmacologic interventions
Lifestyle management, including medical nutrition therapy
(well-balanced diet), physical activity, and weight control, is
recommended for all patients with type 2 diabetes. Decreases
in HbA1c of approximately 1% to 2% have been demonstrated
in randomized controlled clinical trials and observational
studies evaluating medical nutrition therapy. 37 Of note,
a recent systematic review and analysis by Boling et al38
echoed previous suggestions that low-carbohydrate (ie, 40%
energy from carbohydrates), rather than well-balanced, diets
lead to better glycemic control (HbA1c decreases of 0.9%

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Aryangat and Gerich

to 1.5%) and may be the most efficacious dietary strategy

for reducing obesity-related metabolic disease complications.
Similarly, a meta-analysis by Barclay et al39 indicated that low
glycemic index and glycemic load diets result in reduced risk
for type 2 diabetes and heart disease. The most recent and
notable example of the advantages of weight loss, conferred
by increased physical activity and low-calorie/low-fat diets,40
are results from the 10-year follow-up of the Diabetes Prevention Program (DPP) Outcomes Study.41 This follow-up,
prospective analysis included 2766 patients at high risk for
developing type 2 diabetes from the initial DPP trial who
received standard medical information regarding health
risks and type 2 diabetes and placebo, metformin, or intensive lifestyle intervention (for details, consult the published
description of the latter group40). The most significant findings
of this study were that the placebo-adjusted incidences of a
type 2 diabetes diagnosis at 10 years showed 34% and 18%
reductions for the intensive lifestyle intervention and metformin groups, respectively.41 Interestingly, while patients in the
lifestyle intervention and metformin groups tended to lose
weight initially, mean weight of the 3 treatment groups tended
to converge at 10 years, though at a range of 0 to 2.5 kg
change from baseline for all groups.41 However, clinicians
clearly recognize that lifestyle interventions in most patients
are largely ineffective without intensive supervision because it
is difficult for most patients to change their lifestyle or maintain positive lifestyle changes. It has been shown that patients
with higher perceived and actual risks of developing diabetes
did not intend to adopt healthier lifestyle behaviors more
readily than those with lower perceived and actual risks,42
though if followed closely with physician monitoring and
clinical support, patients can indeed reap the benefits (eg, risk
reduction of developing diabetes) of such alterations.3941,43
Unfortunately, intensive treatment approaches are costly44,45
making them unpopular amidst the current economic crises
worldwide and ever rising health care costs in the United
States. Some efforts to reduce costs by using community
resources or motivational techniques have shown promising
results,46,47 but are far from large-scale implementation.

Surgical intervention
Obesity, superimposed on a genetic -cell defect, is the
main cause for the increased prevalence of type 2 diabetes.48
Bariatric surgery is a growing weight loss option for obese
people who have failed lifestyle and diet pill interventions.
The National Institutes of Health (NIH) guidelines require
bariatric surgery candidates to have a body mass index
(BMI) 40 kg/m2 (severe obesity) or a BMI between 35 and

150

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39.9 kg/m2 with a serious obesity-related health problem such

as type 2 diabetes, coronary heart disease, or severe sleep
apnea.49 This is unconscionable considering some healthcare providers believe that the NIH guideline should be less
restrictive, given the considerable health and cost benefits
of bariatric surgery.50
Bariatric surgery has dramatic effects on glycemic
control. For example, in a randomized controlled trial with
60 obese patients (BMI 30 and 40 kg/m2) with type 2
diabetes 2 years, half the patients had laparoscopic adjustable gastric banding with conventional diabetes care; the
other half had conventional diabetes therapy with lifestyle
changes. Among patients who completed the 2-year followup, 73% in the surgical group versus 13% in the control
group achieved remission of type 2 diabetes.51 A 10-year
study comparing conventional (nonsurgical) treatment with
bariatric surgery showed recovery from diabetes in 72% of
patients in the bariatric surgical group, compared with 21%
in the nonsurgical group after 2 years.52 Furthermore, a
cost-analysis study indicates that there is a return on investment in 2 to 5 years postsurgery with respect to the costs
associated with comorbidities in morbidly obese patients,
including those with type 2 diabetes, CAD, hypertension,
and sleep apnea.50 While this strategy is gaining further
popularity among patients with BMI 35 kg/m2, long-term
studies among the dysglycemic subpopulation are needed to
ascertain whether this strategy can be applied universally to
obese patients with postprandial hyperglycemia.

Pharmacologic interventions
The classes of drugs for the treatment of type 2 diabetes that primarily target postprandial hyperglycemia are
summarized in Table 2.6,11,53 The 2 newest classes of antidiabetic agents dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) analogs are
incretin-based therapies. The incretin hormones, GLP-1
and glucose-dependent insulinotropic polypeptide (GIP),
are released from the small intestine during absorption
of meals and increase pancreatic secretion of insulin.54
GLP-1, but not GIP, suppresses glucagon release from the
pancreatic -cells. In type 2 diabetes, incretin hormone
function is impaired,54 resulting in less insulin release and
more glucagon secretion after meals.55 More glucose enters
the circulation, but there is less efficient glucose removal,
higher plasma glucose levels, and hence, acute oxidative
stress.22,55 Disease-related complications associated with
oxidative stress may be reduced with agents that target postprandial hyperglycemia.

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Acarbose is largely unabsorbed

from the intestine, whereas
miglitol is absorbed from the
intestine

2) Miglitol (Glyset,
Bayer HealthCare
Pharmaceuticals Inc.)

25 mg100 mg TID prior to each meal

25 mg100 mg TID prior to each meal

2) Liraglutide (Victoza)
Novo Nordisk

1.8 mg od injection independent of meals

The analog simulates the activity

1) Exenatide (Byetta,
5 g10 g BID injections any time within
Amylin Pharmaceuticals, of GLP-1, namely insulin secretion 60 minutes before morning and evening meals
Inc.)
in a glucose-dependent fashion;
inhibits hyperglucagonemia, slows
gastric emptying, reduces appetite,
and improves satiety, peak of
action

GLP-1 analogs

Inhibits the terminal step of

carbohydrate digestion at the
brush border level of the small
intestine thereby shifting and
delaying absorption

1) Acarbose

-Glucosidase
inhibitors

120 mg TID; 60 mg TID, give 130 minutes

prior to each meal

A phenylalanine derivative

2) Nateglinide
(Starlix, Novartis
Pharmaceuticals
Corporation)

Dosage

0.5 mg2 mg TID, maximum 16 mg daily,

give 1530 minutes prior to each meal

Mechanism of action

1) Repaglinide (Prandin, Meglitinide family, short half-life

Novo Nordisk Inc.)
and binds to a SUR1 site, closing
KATP channels of the pancreatic
-cells, stimulating insulin release

Glinides

Agent

~1.01.3c

0.51.0

~1.72.7c

3.6

4.0

N/A

0.50.8

0.40.8

2.6 mmol/L

0.61.5

Comments/contraindications

As exenatide
(above)

Nausea,
vomiting,
acute
pancreatitis

Flatulence,
abdominal
distress or
diarrhea

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(Continued)

As exenatide (above); also use as

monotherapy; contraindicated in
MTC or multiple endocrine neoplasia
syndrome type 2

In patients with a history of

pancreatitis, other diabetic agents
should be considered
Can be used as adjunct treatment in
patients with type 2 diabetes who
take metformin, a sulfonylurea, or a
thiazolidinedione, or with a combination of metformin and a sulfonylurea
or thiazolidinedione. Decrease in body
weight
No long-term safety studies at this
time

AGIs specifically help PPG, but have

little effect on FPG; contraindicated in
patients with chronic intestinal
conditions, especially inflammatory
bowel disease

Lower potential for

hypoglycemia, but lower overall
glucose-lowering effectiveness

Hypoglycemia, Long residence time on the SUR53 and

weight gain
prolonged blood glucoselowering
effects if used concomitantly with
gemfibrozil

HbA1c
PPG reduction, Adverse
reduction,a % mmol/L
effects

Table 2 Profiles of agents currently approved in the US (unless otherwise indicated) primarily targeting postprandial hyperglycemia6,11,53

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T2D: postprandial hyperglycemia and increased CV risk

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Hypoglycemia
and weight
gain

As sitagliptin
(above)

Upper
respiratory
tract infection
and naso
pharyngitis

Current status: under FDA review

Current status: approved in Europe

As sitagliptin (above)

No long-term safety studies at this

time
No serious adverse reactions
reported to date
Weight neutral

Current status: in phase III

development

Comments/contraindications

Assuming an initial HbA1c of at least 8%.

Lispro (Humalog, Eli Lilly and Company).
c
Exenatide and liraglutide HbA1c efficacy based on combination therapy.
Data obtained from each products respective package insert and Nathan DM et al.6
Abbreviations: AGI, -glucosidase inhibitor; BID, twice daily; CrCL, creatinine clearance; DPP-4, dipeptidyl peptidase-4; FPG, fasting plasma glucose; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1;
KATP, potassium adenosine triphosphate; MTC, medullary thyroid carcinoma; PBO, placebo; PPG, postprandial glucose; SUR, sulfonylurea receptor; TID, 3 times daily.

N/A vs PBO

11 (not PBO
corrected)b

3) Glulisine (Apidra,
sanofi-aventis US LLC)

Variable
depending on
aggressiveness
of titration

As sitagliptin
(above)

2.8

N/A

Individualized

As sitagliptin
(above)

0.60.8

HbA1c
PPG reduction, Adverse
reduction,a % mmol/L
effects

2) Aspart (NovoLog,
Novo Nordisk)

1) Lispro (Humalog,
Eli Lilly and Company)

Suppresses glucose production

and increases efficiency of tissue
glucose uptake

4) Alogliptin

Rapid-acting insulins

50 mg BID, max 100 mg

N/A

3) Vildagliptin

100 mg once daily with or without food.

In patients with moderate renal insufficiency
(CrCL 30 to 50 mL/min) reduce dosage
to 50 mg daily. In patients with severe renal
insufficiency or end-stage renal disease
(CrCL is 30 mL/min) reduce dosage
to 25 mg daily

Dosage

2.5 mg or 5 mg once daily regardless of

meals
2.5 mg is recommended for patients
with moderate or severe renal impairment,
or end-stage renal disease (CrCL 50 mL/min).
2.5 mg is recommended for patients also taking
strong cytochrome P450 3A4/5 inhibitors

Inhibits DPP-4 enzyme, and

thereby produces moderate
increases in GLP-1 and GIP

Expected duration of action

1 week

Mechanism of action

2) Saxagliptin (Onglyza,
Bristol-Myers Squibb/
AstraZeneca)

1) Sitagliptin (Januvia,
Merck & Co., Inc.)

DPP-4 inhibitors

3) Exenatide
sustained release

Agent

Table 2 (Continued)

Aryangat and Gerich

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Vascular Health and Risk Management 2010:6

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GLP-1 analogs
Endogenous GLP-1 is rapidly cleared (12 minutes) by the
enzyme DPP-4; therefore, the natural form is not practical as
a therapeutic intervention in type 2 diabetes management.56
Injectable GLP-1 analogs are resistant to DPP-4 and thus, have
a longer half-life than endogenous GLP-1. GLP-1 analogs
increase glucose-dependent insulin secretion and decrease
glucagon secretion, leading to PPG control, delayed gastric
emptying, and increased satiety, potentially leading to weight
loss. Exenatide (Byetta, Amylin Pharmaceuticals, Inc.) and
liraglutide (Victoza; Novo Nordisk) are injected twice daily
and once daily, respectively. Their use in combination lowers
HbA1c by approximately 0.5% to 1.0%.6,57 Both agents are
approved for use in combination with metformin, a sulfonylurea (SU), and/or a thiazolidinedione (TZD); liraglutide is also
available as monotherapy in the United States.6,57 Both agents
are associated with gastrointestinal (GI) side effects, including
diarrhea, vomiting, and nausea and there is also an association with acute pancreatitis.6,57 Therefore, the Food and Drug
Administration recommends that in a patient with diabetes who
has a history of pancreatitis, other antidiabetic agents should be
considered.57,58 For liraglutide, the US prescribing information
includes a boxed warning for the risk of thyroid C-cell tumors.57
A sustained-release form of exenatide, with duration of up to
one week is currently in late-phase development.59,60

DPP-4 inhibitors
The DPP-4 inhibitors sitagliptin and saxagliptin were approved
in 2006 and 2009, respectively. Vildagliptin, another DPP-4
inhibitor, is currently approved outside the United States. DPP4 inhibitors, like GLP-1 analogs, mechanistically decrease PPG
and have a low propensity for hypoglycemia or weight gain.6163
Alogliptin, dutogliptin, and linagliptin are other DPP-4 inhibitors in various stages of development. These DPP-4 inhibitors
have been studied as monotherapy as well as in combination
with metformin, SUs, and TZDs. DPP-4 inhibitors have fewer
GI side effects than GLP-1 analogs.61,63

Rapid-acting insulins
Rapid-acting insulins (lispro, aspart, or glulisine) improve PPG
when administered before a meal.29,64,65 An alternative would be
pre-breakfast and pre-dinner premix insulins containing a rapidacting insulin and a long-acting insulin.66 These latter insulin regimens, however, are less flexible and are associated with greater
risk of hypoglycemia than rapid-acting insulin regimens.66

Guideline update
In 2009, the AACE released a new treatment algorithm.
While there were no changes to the placement of insulin in

Vascular Health and Risk Management 2010:6

T2D: postprandial hyperglycemia and increased CV risk

the algorithm (ie, last line of therapy after oral antidiabetic

drug use), the new recommendations advocate the early
use of the incretin-based therapies GLP-1 analogues and
DPP-4 inhibitors.67 More specifically, incretin-based therapies are recommended as monotherapy for patients with
HbA1c 6.5% to 7.5%, which most closely corresponds to the
HbA1c range previously identified to be most impacted by
PPG targeting.7,28

Conclusions
Substantial evidence has accumulated indicating that chronic
hyperglycemia is a risk factor for micro- and macrovascular
disease. Observational studies indicate that isolated postprandial hyperglycemia increases CV mortality. Various
antihyperglycemic agents now exist that preferentially target postprandial hyperglycemia (meglitinides, rapid-acting
insulin analogs, GLP-1 agonists, and DPP-4 inhibitors) and
afford physicians a choice of treatment options that can
now be based on individual patient profiles. Controlling
and achieving target goals early in the course of diabetes
has been shown to provide better outcomes in terms of CV
risk. Postprandial glucose should be normalized along with
FPG to achieve the currently recommended goal of HbA1c
7%. As reflected in recent trials, a less intense goal may be
needed for certain subpopulations of patients with diabetes
who have a history of severe CVD, severe hypoglycemia,
advanced age, or advanced microvascular or macrovascular
complications. Target levels of glucose control should be
individualized by focusing on both FPG and PPG and by
optimizing other risk factors of CVD, including high blood
pressure, hyperlipidemia, obesity, smoking, and poor exercise
and dietary habits.

Acknowledgments
Technical and editorial assistance for this manuscript was
provided by Trina Ricci, PhD, of Quintiles.

Funding source
Technical and editorial assistance was funded by BristolMyers Squibb and AstraZeneca. The authors received no
remuneration and are solely responsible for the content.

Disclosures
Dr Aryangat has nothing to declare. Dr Gerich has served on
advisory boards and/or speakers bureaus for, and has received
honoraria or consulting fees from, Amylin Pharmaceuticals,
AstraZeneca, Bristol-Myers Squibb, Centocor, Daiichi
Sankyo, Eisai, Elixir, Forest Laboratories, GlaxoSmithKline,

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153

Aryangat and Gerich

Johnson & Johnson, Kowa, LifeScan, MannKind Corporation, Merck, Novartis, Novo Nordisk, Pfizer, sanofi-aventis,
and Sirtris Pharmaceuticals. Dr Gerich has received grant
support from Boehringer Ingelheim, Bristol-Myers Squibb,
Daiichi Sankyo, GlaxoSmithKline, Kowa, Novartis, Novo
Nordisk, Pfizer, sanofi-aventis, and Sirtris Pharmaceuticals.
Dr Gerich has received grant support from Boehringer
Ingelheim, Bristol-Myers Squlbb, Daiichi Sankyo, GlaxoSmithKline, Kowa, Novartis, Novo Nordisk, Pfizer, sanofiaventis, and Takeda, and served on the rimonabant data safety
monitoring board for sanofi-aventis.

References

1. UK Prospective Diabetes Study (UKPDS) Group. Intensive bloodglucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2
diabetes (UKPDS 33). Lancet. 1998;352:837853.
2. Patel A, MacMahon S, Chalmers J, et al; for the ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in
patients with type 2 diabetes. N Engl J Med. 2008;358:25602572.
3. The Writing Team for the Diabetes Control and Complications Trial/
Epidemiology of Diabetes Interventions and Complications Research
Group. Effect of intensive therapy on the microvascular complications
of type 1 diabetes mellitus. JAMA. 2002;287:25632569.
4. American Diabetes Association. Standards of medical care in diabetes
2009. Diabetes Care. 2009;32(Suppl 1):S13S61.
5. Rodbard HW, Blonde L, Braithwaite S, et al. American Association of
Clinical Endocrinologists medical guidelines for clinical practice for the
management of diabetes mellitus. Endocr Pract. 2007;13(suppl 1):168.
6. Nathan DM, Buse JB, Davidson MB, et al. Medical management of
hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American
Diabetes Association and the European Association for the Study of
Diabetes. Diabetes Care. 2009;32:193203.
7. Woerle HJ, Neumann C, Zschau S, et al. Impact of fasting and postprandial glycemia on overall glycemic control in type 2 diabetes: importance
of postprandial glycemia to achieve target HbA1c levels. Diabetes Res
Clin Pract. 2007;77:280285.
8. Malmberg K, Rydn L, Wedel H, et al; for the DIGAMI 2 Investigators. Intense metabolic control by means of insulin in patients with
diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects
on mortality and morbidity. Eur Heart J. 2005;26:650661.
9. Dale AC, Vatten LJ, Nilsen TI, Midthjell K, Wiseth R. Secular decline in
mortality from coronary heart disease in adults with diabetes mellitus:
cohort study. BMJ. 2008;337:a236.
10. Yusuf S, Hawken S, unpuu S, et al; for the INTERHEART Study
Investigators. Effect of potentially modifiable risk factors associated
with myocardial infarction in 52 countries (the INTERHEART study):
case-control study. Lancet. 2004;364:937952.
11. Gerich JE. Clinical significance, pathogenesis, and management of
postprandial hyperglycemia. Arch Intern Med. 2003;163:13061316.
12. Cavalot F, Petrelli A, Traversa M, et al. Postprandial blood glucose is a
stronger predictor of cardiovascular events than fasting blood glucose in
type 2 diabetes mellitus, particularly in women: lessons from the San Luigi
Gonzaga Diabetes Study. J Clin Endocrinol Metab. 2006;91:813819.
13. Tominaga M, Eguchi H, Manaka H, Igarashi K, Kato T, Sekikawa A;
for the Funagata Diabetes Study. Impaired glucose tolerance is a risk
factor for cardiovascular disease, but not impaired fasting glucose.
Diabetes Care. 1999;22:920924.
14. Gerstein HC, Miller ME, Byington RP, et al; for the Action to Control
Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:25452559.

154

submit your manuscript | www.dovepress.com

Dovepress

Dovepress
15. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year
follow-up of intensive glucose control in type 2 diabetes. N Engl J Med.
2008;359:15771589.
16. Nathan DM, Cleary PA, Backlund JY, et al; for the Diabetes Control
and Complications Trial/Epidemiology of Diabetes Interventions and
Complications (DCCT/EDIC) Study Research Group. Intensive diabetes
treatment and cardiovascular disease in patients with type 1 diabetes.
N Engl J Med. 2005;353:26432653.
17. Duckworth W, Abraira C, Moritz T, et al; for the VADT Investigators.
Glucose control and vascular complications in veterans with type 2
diabetes. N Engl J Med. 2009;360:129139.
18. Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the
ACCORD, ADVANCE, and VA diabetes trials: a position statement
of the American Diabetes Association and a scientific statement of the
American College of Cardiology Foundation and the American Heart
Association. Diabetes Care. 2009;32:187192.
19. Monnier L, Mas E, Ginet C, et al. Activation of oxidative stress by acute
glucose fluctuations compared with sustained chronic hyperglycemia
in patients with type 2 diabetes. JAMA. 2006;295:16811687.
20. Ceriello A, Esposito K, Piconi L, et al. Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in
normal and type 2 diabetic patients. Diabetes. 2008;57:13491354.
21. Beckman JA, Goldfine AB, Gordon MB, Creager MA. Ascorbate
restores endothelium-dependent vasodilation impaired by acute hyperglycemia in humans. Circulation. 2001;103:16181623.
22. Monnier L, Colette C. Glycemic variability: should we and can we
prevent it? Diabetes Care. 2008;31(suppl 2):S150S154.
23. Shimabukuro M, Higa N, Chinen I, Yamakawa K, Takasu N. Effects of
a single administration of acarbose on postprandial glucose excursion
and endothelial dysfunction in type 2 diabetic patients: a randomized
crossover study. J Clin Endocrinol Metab. 2006;91:837842.
24. Weinbaum S, Zhang X, Han Y, Vink H, Cowin SC. Mechanotransduction
and flow across the endothelial glycocalyx. Proc Natl Acad Sci U S A.
2003;100:79887995.
25. Noble MI, Drake-Holland AJ, Vink H. Hypothesis: arterial glycocalyx
dysfunction is the first step in the atherothrombotic process. QJM.
2008;101:513518.
26. Nieuwdorp M, Van Haeften TW, Gouverneur MC, et al. Loss of
endothelial glycocalyx during acute hyperglycemia coincides with
endothelial dysfunction and coagulation activation in vivo. Diabetes.
2006;55:480486.
27. Brownlee M. The pathobiology of diabetic complications: a unifying
mechanism. Diabetes. 2005;54:16151625.
28. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia
of type 2 diabetic patients: variations with increasing levels of HbA1c.
Diabetes Care. 2003;26:881885.
29. Holman RR, Farmer AJ, Davies MJ, et al. Three-year efficacy of complex
insulin regimens in type 2 diabetes. N Engl J Med. 2009;361:17361747.
30. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M, for
the STOP-NIDDM Trial Research Group. Acarbose treatment and the risk
of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA. 2003;290:486494.
31. Esposito K, Ciotola M, Carleo D, et al. Post-meal glucose peaks at home
associate with carotid intima-media thickness in type 2 diabetes. J Clin
Endocrinol Metab. 2008;93:13451350.
32. Mita T, Watada H, Shimizu T, et al. Nateglinide reduces carotid intimamedia thickening in type 2 diabetic patients under good glycemic
control. Arterioscler Thromb Vasc Biol. 2007;27:24562462.
33. Hanefeld M, Chiasson JL, Koehler C, Henkel E, Schaper F, TemelkovaKurktschiev T. Acarbose slows progression of intima-media thickness of
the carotid arteries in subjects with impaired glucose tolerance. Stroke.
2004;35:10731078.
34. Iijima R, Nakajima R, Sugi K, Nakamura M. Improvement of
postprandial hyperglycemia has a positive impact on epicardial flow
of entire coronary tree in acute coronary syndromes patients. Circ J.
2007;71:10791085.
Vascular Health and Risk Management 2010:6

Dovepress
35. Scognamiglio R, Negut C, De Kreutzenberg SV, Tiengo A, Avogaro A.
Postprandial myocardial perfusion in healthy subjects and in type 2
diabetic patients. Circulation. 2005;112:179184.
36. International Diabetes Federation. Guideline for management of postmeal glucose. Brussels, Belgium: International Diabetes Federation;
2007. http://www.idf.org/webdata/docs/Guideline_PMG_final.pdf.
Accessed November 24, 2009.
37. Pastors JG, Warshaw H, Daly A, Franz M, Kulkarni K. The evidence for
the effectiveness of medical nutrition therapy in diabetes management.
Diabetes Care. 2002;25:608613.
38. Boling CL, Westman EC, Yancy WS Jr. Carbohydrate-restricted diets
for obesity and related diseases: an update. Curr Atheroscler Rep.
2009;11:462469.
39. Barclay AW, Petocz P, Millan-Price J, et al. Glycemic index, glycemic
load, and chronic disease riska meta-analysis of observational studies.
Am J Clin Nutr. 2008;87:627637.
40. Diabetes Prevention Program Research Group. The Diabetes Prevention
Program (DPP): description of lifestyle intervention. Diabetes Care.
2002;25:21652171.
41. Diabetes Prevention Program Research Group, Knowler WC, Fowler
SE, Hamman RF, et al. 10-year follow-up of diabetes incidence and
weight loss in the Diabetes Prevention Program Outcomes Study.
Lancet. 2009;374:16771686.
42. Hivert MF, Warner AS, Shrader P, Grant RW, Meigs JB. Diabetes risk
perception and intention to adopt healthy lifestyles among primary care
patients. Diabetes Care. 2009;32:18201822.
43. Ratner R, Goldberg R, Haffner S, et al. Impact of intensive lifestyle and
metformin therapy on cardiovascular disease risk factors in the diabetes
prevention program. Diabetes Care. 2005;28:888894.
44. Diabetes Prevention Program. Within-trial cost-effectiveness of lifestyle
intervention or metformin for the primary prevention of type 2 diabetes.
Diabetes Care. 2003;26:25182523.
45. Lindgren P, Lindstrom J, Tuomilehto J, et al. Lifestyle intervention to
prevent diabetes in men and women with impaired glucose tolerance
is cost-effective. Int J Technol Assess Health Care. 2007;23:177183.
46. Ackermann RT, Finch EA, Brizendine E, Zhou H, Marrero DG. Translating the Diabetes Prevention Program into the community. The DEPLOY
Pilot Study. Am J Prev Med. 2008;35:357363.
47. Greaves CJ, Middlebrooke A, OLoughlin L, et al. Motivational interviewing for modifying diabetes risk: a randomised controlled trial.
Br J Gen Pract. 2008;58:535540.
48. Romao I, Roth J. Genetic and environmental interactions in obesity and
type 2 diabetes. J Am Diet Assoc. 2008;108:S24S28.
49. National Institute of Diabetes and Digestive and Kidney Diseases.
Bariatric surgery for severe obesity. Weight-Control Information Network Web site. NIH Publication No. 08-4006. http://win.niddk.nih.
gov/publications/gastric.htm. Accessed November 24, 2009.
50. Crmieux P-Y, Buchwald H, Shikora SA, Ghosh A, Yang HE, Buessing M.
A study on the economic impact of bariatric surgery. Am J Manag Care.
2008;14:589596.
51. Dixon JB, OBrien PE, Playfair J, et al. Adjustable gastric banding and
conventional therapy for type 2 diabetes: a randomized controlled trial.
JAMA. 2008;299:316323.
52. Sjstrm L, Lindroos A-K, Peltonen M, et al; for the Swedish Obese
Subjects Study Scientific Group. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med.
2004;351:26832693.

T2D: postprandial hyperglycemia and increased CV risk

53. Hu S, Wang S, Fanelli B, et al. Pancreatic cell KATP channel activity
and membrane-binding studies with nateglinide: a comparison with sulfonylureas and repaglinide. J Pharmacol Exp Ther. 2000;293:444452.
54. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1
receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:16961705.
55. Mitrakou A, Kelley D, Veneman T, et al. Contribution of abnormal
muscle and liver glucose metabolism to postprandial hyperglycemia
in NIDDM. Diabetes. 1990;39:13811390.
56. Drucker DJ. Enhancing incretin action for the treatment of type 2
diabetes. Diabetes Care. 2003;26:29292940.
57. Victoza [package insert]. Bagsvaerd, Denmark: Novo Nordisk A/S;
January 2010.
58. US Food and Drug Administration/Center for Drug Evaluation and Research. Exenatide (marketed as Byetta)Healthcare
professional sheet text version (8/2008). FDA Web site. Updated
August 18, 2008. http://www.fda.gov/Dr ugs/Dr ugSafety/
PostmarketDrugSafetyInformationforPatientsandProviders/
ucm124713.htm. Accessed November 24, 2009.
59. Vilsbll T, Zdravkovic M, Le-Thi T, et al. Liraglutide, a long-acting
human glucagon-like peptide-1 analog, given as monotherapy significantly improves glycemic control and lowers body weight without
risk of hypoglycemia in patients with type 2 diabetes. Diabetes Care.
2007;30:16081610.
60. Nauck MA, Hompesch M, Filipczak R, Le TD, Zdravkovic M,
Gumprecht J; for the NN2211-1499 Study Group. Five weeks of treatment with the GLP-1 analogue liraglutide improves glycaemic control
and lowers body weight in subjects with type 2 diabetes. Exp Clin
Endocrinol Diabetes. 2006;114:417423.
61. Rosenstock J, Sankoh S, List JF. Glucose-lowering activity of the
dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naive patients with
type 2 diabetes. Diabetes Obes Metab. 2008;10:376386.
62. Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, WilliamsHerman DE; for the Sitagliptin Study 021 Group. Effect of the dipeptidyl
peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in
patients with type 2 diabetes. Diabetes Care. 2006;29:26322637.
63. Pi-Sunyer FX, Schweizer A, Mills D, Dejager S. Efficacy and tolerability
of vildagliptin monotherapy in drug-naive patients with type 2 diabetes.
Diabetes Res Clin Pract. 2007;76:132138.
64. Gough SCL. A review of human and analogue insulin trials. Diabetes
Res Clin Pract. 2007;77:115.
65. Giugliano D, Ceriello A, Razzoli E, Esposito K. Defining the role
of insulin lispro in the management of postprandial hyperglycaemia
in patients with type 2 diabetes mellitus. Clin Drug Investig. 2008;
28:199210.
66. Ilag LL, Kerr L, Malone JK, Tan MH. Prandial premixed insulin
analogue regimens versus basal insulin analogue regimens in the management of type 2 diabetes: an evidence-based comparison. Clin Ther.
2007;29:12541270.
67. Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by an American
Association of Clinical Endocrinologists/American College of Endocrinology Consensus Panel on type 2 diabetes mellitus: an algorithm
for glycemic control. Endocr Pract. 2009;15:541559.

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